The heart-lung machine is a system used for cardiopulmonary bypass (“CPB”). Since the development of a prototype system by Dr. John Gibbon in 1953, the use of CPB has evolved to the point where it is now commonplace, and permits major surgical procedures to be performed on the heart.
While on bypass, the blood flow is diverted around the heart and lungs, as a machine takes over the responsibility of both oxygenating the blood and maintaining blood flow. Cardiopulmonary bypass permits the surgeon to operate on the heart while the heart-lung machine sustains circulation throughout the body. Oxygen-poor blood that would normally enter the heart through the superior and inferior vena cavae, is shunted off through the superior vena caval cannula and the inferior vena caval cannula. Once oxygenated, the blood is returned to the body through the aortic cannula.
The typical CPB circuit includes several components, including one or more oxygenators, heat exchangers, tubing sets, filters, pumps and reservoirs. The circuit is often used, in turn, in combination with one or more drugs such as heparin, which is an anticoagulant that is both administered intravenously and can be used to coat blood contacting surfaces. At the conclusion of surgery, the presence and effect of heparin is reversed, typically in a rapid manner, by the administration of a drug such as protamine. Protamine, which is derived from salmon sperm, is highly positively charged and serves to effectively neutralize the negatively charged heparin in a cationic/anionic interaction. Protamine, however, has its own drawbacks, in the form of potential allergenic and inflammatory responses.
Extracorporeal circulation, such as that used during cardiopulmonary bypass, continues to be associated with various drawbacks, however, including both inflammation and excessive bleeding. The inflammatory response is believed to be caused, or exacerbated, by various factors, including the various flow forces (e.g., shear associated with turbulence and suction) involved in CPB, and by the exposure of blood to both foreign surfaces and to air. Exposure of the blood to oxygenators, pumps, and blood salvage and tubing sets, is well documented to activate inflammation responses during and post bypass procedures. In addition, the process of removing the anticoagulant heparin, post bypass, by addition of protamine is also documented to activate inflammatory processes. Inflammation, in turn, can cause both cell damage and diminished organ function, leading to increased morbidity and a longer recovery time with an increase in both length of hospital stay and costs.
Inflammatory injury occurs when the patient's own blood, after circulating through the CPB circuit is returned to the patient. The inflammation reaction induced by extracorporeal circulation also has the potential of increasing patient risk of inducing the “whole body inflammatory response” and ensuing organ failure. Approximately 600,000 cardiac surgical procedures requiring CPB are performed annually in North America and approximately 400,000 in the rest of the world. Most, if not all, of such procedures involve the need to monitor both heparin concentration and whole blood Activated Clotting Time (ACT).
As mentioned above, the use of heparin and protamine may be associated with a number of adverse effects. Close monitoring of the heparin concentration and clotting time is required due to risk of clotting, if the heparin levels drop excessively low. Similarly, excessively high levels of heparin can require correspondingly high dosages of protamine. Although life-threatening, protamine-related reactions occur in less than 5% of cardiac surgical patients. Still, the use of protamine is broadly problematic and severe reactions to protamine complex are idiosyncratic.
Moreover, protamine is difficult to titrate. The existence of many dosing regimes attests to the fact there is no agreement among practitioners as to how best the drug should be used. Protamine may be dosed on the basis of 1) body weight or surface area, 2) by a fixed ratio to the initial dose of heparin, 3) by fixed ratio according to the total heparin dose, or 4) by response to the activated clotting time (ACT). Because protamine itself has anticoagulant properties when given in excess, the ideal protamine dose results in plasma levels just exceeding the heparin concentration. However, there is evidence that fixed-ratio dosing schemes tend to result in excessive protamine administration.
While the ACT is used as a functional test for the adequacy of heparin reversal, it does not provide an index of how much protamine is required to reverse heparin. This is, in part a function of large patient-to-patient variability in heparin pharmacodynamics and pharmacokinetics (e.g., the half-life for heparin may vary for 30 min to 2 hr). While this functional test is used in practice when bleeding is present, additional repeated doses of protamine are often given even when the ACT is normal.
These and other complications associated with heparin and protamine dictate that management of patient's heparin concentration and clotting time be closely monitored. Typically, however, heparin concentration is not accurately recorded during CPB, due largely to the lack of suitable methods and instrumentation. At most, some facilities measure a heparin concentration “range” by removing plasma and performing a heparin determination by protamine titration, using a commercially available device. Such an approach has several drawbacks, however, including the lack of a direct measurement of heparin concentration, the need for manual blood draws, and heparin concentrations that are provided in gross increments.
Another complication of surgical procedures that involve CPB is excessive bleeding. A recently approved drug known as aprotinin can effectively reduce blood loss and decrease the need for transfusions. Aprotinin was studied for use mainly in heart surgery because the circulation of the blood outside the body in this surgery increases the likelihood of excessive bleeding during and after surgery.
Aprotinin (Trayslol™, Bayer) is a natural protease inhibitor derived from bovine lung, and acts by inhibiting trypsin, chymotrypsin, plasmin, tissue plasminogen activator, and kallikrein, thereby directly affecting fibrinolysis. It also inhibits the contact phase activation of coagulation which initiates coagulation and promotes fibrinolysis. In addition, aprotinin preserves the adhesive glycoproteins in the platelet membrane, rendering them resistant to damage from the increased plasmin levels and mechanical injury that occur during cardiopulmonary bypass. The net effect is to inhibit both fibrinolysis and turnover of coagulation factors and to decrease bleeding. T1/2, IV: 150 min with a terminal elimination phase half-life of 10 hr. Aprotinin is slowly broken down by lysosomal enzymes, although depending on the dose, up to 9% may be excreted through the urine unchanged.
Although aprotinin was studied in the 1960's, low doses were evaluated in an effort to treat bleeding after cardiac surgery rather than to prevent it. However, it was not until the late 1980's that prothylactic use was reported. Royston developed a pharmacologic approach to inhibit inflammatory responses during CPB administering that includes a loading dose of 2 million units of aprotinin following intubation, and a continuous infusion of 500,000 units/hour with a CPB pump prime dose of 2 million units. This has become known as the high dose or “Hammersmith regimen”. In patient's receiving aprotinin, chest tube drainage was 286 ml as compared to 1509 ml in the control.
In the United States approximately 20% of all CPB cases presently also incorporate the use of aprotinin, while in Europe about 80% of CPB cases presently use aprotinin. Postoperative bleeding is a cause of morbidity and mortality in this patient population. Extracorporeal circulation makes cardiac surgery possible but requires complete anticoagulation with heparin because the CPB apparatus and procedure is thrombogenic. During CPB, systemic anticoagulation is achieved with a loading dose of heparin (300–400 IU/kg) to achieve an Activated Clotting Time (ACT) of >500 seconds (normal non anticoagulated blood has an ACT time range of 80–110 seconds). This anticoagulation level of >500 seconds is targeted so as to preserve normal blood fluidity and limit blood clot formation to vascular injury sites. At the completion of the CPB case, the circulating heparin is reversed with protamine sulfate. While the ACT is used as a functional test for the adequacy of heparin reversal, it does not provide an index of how much protamine is required to reverse heparin. This is in part a function of large patient-to-patient variability in heparin pharmacodynamics and pharmacokinetics (the half-life for heparin may vary for 30 min to 2 hr). While this functional test is used in practice when bleeding is present, additional repeated doses of protamine are often given when the ACT is normal.
In redo CABG patients, Cosgrove, et al., (Ann. Thorac. Surg. 54:1031–1038, 1992) reported 171 patients who received either high dose aprotinin (Hammersmith dose), low dose aprotinin (half Hammersmith dose), or placebo. They found that low dose aprotinin was as effective as high dose aprotinin in decreasing blood loss and blood transfusion requirements. In contrast, Levy et al. (Anesth. Analg. 81:35–37, 1995) also reported the use of four different treatment groups in 287 patients undergoing repeat CABG surgery. Transfusion of allogenic packed RBC's was significantly less in the aprotinin treated patients compared to the placebo, with even greater reductions in total blood products exposure in high dose and half dose groups compared to placebo or pump prime cohorts.
The Full Hammersmith regimen of aprotinin reduces transfusion requirements and results in aprotinin concentrations reported to be in the range of 127–191 Kallikrein Inhibitory Units per millilter (“KIU/mL”) at the end of one to two hours of CPB. This dosing regimen calls for an infusion of 0.5×106 KIU per hour from skin incision to completion of surgery in addition to 2×106 KIU added to the CPB pump prime solution. This dosing regimen attempts to maintain a plasma aprotinin concentration of 200 KIU/mL during CPB. Although concentrations of approximately 50 KIU/mL decrease fibrinolysis through inhibition of plasmin, a higher concentration (approx. 200 KIU/mL) appears to be necessary in order to inhibit kallikrein.
As recently reported by E. Bennett-Gurrero, et al., in the Annals of Thoracic Surgery, aprotinin concentrations in the range of 127–191 kallikrein inactivator units (KIU) at the end of CPB (<2 hr duration) reduce transfusion requirements. It has been suggested that prolonged CPB may require higher infusion rates which significantly increase cost. Bennet-Guerrero reported that the cost for aprotinin given according to the Full Hammersmith regimen is $900–$ 1200 at Duke University Medical Center. The Duke group measured KIU and maintained these values between 127–191 KIU/mL.
There is no dispute that aprotinin reduces postoperative blood loss, however the dose regimen practices vary widely. Practice varies with the use of aprotinin in the prime, and use of either Full or Half Hammersmith. The parameters of successful levels of aprotinin protection are best measured in KIU. The dose of aprotinin obviously is related to the effect of the protease aprotinin on inhibition of kallikrein.
Since there is currently no way to provide a real time monitor for either aprotinin, per se, or its metabolic effectiveness, aprotinin tends to be provided in large doses and at multiple times during the CPB surgery, this in spite of its high cost. For instance, an initial test dose must be given 10 min prior to the loading dose. The test dose is followed by a loading dose, which is then followed by a constant infusion dose. In addition, a “pump prime” dose is added to the priming fluid of the cardiopulmonary bypass circuit by replacing an aliquot of the priming fluid prior to beginning cardiopulmonary bypass.
In spite of these and other advances, both inflammation and excessive bleeding continue to be common problems that plague the use of CPB. There clearly remains a need for new approaches to lessen or eliminate the inflammation that occurs in the course of CPB and other medical techniques that involve the extracorporeal circulation of blood.